Method of making porphyrins

ABSTRACT

A method of making a compound of Formula I: 
     
       
         
         
             
             
         
       
     
     is carried out by condensing a pair of compounds of Formula II (which pair may be the same or different), or by condensing a compound of Formula III with a compound Formula IV, 
     
       
         
         
             
             
         
       
     
     to produce a compound of Formula I. The condensing step may be carried out with a metal salt under basic conditions.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication Ser. No. 60/893,002, filed Mar. 5, 2007, the disclosure ofwhich is incorporated by reference herein in its entirety.

This application is related to Lindsey et al., Synthetic Route toABCD-Porphyrins, Filed Feb. 12, 2007 (attorney docket no. 5051-759pr),the disclosure of which is incorporated by reference herein in itsentirety.

This invention was made with Government Support under Grant NumberGM36238 from the National Institutes of Health. The Government hascertain rights to this invention.

FIELD OF THE INVENTION

The present invention concerns methods of making porphyrins, includingboth porphines and trans A₂B₂-porphyrins.

BACKGROUND OF THE INVENTION

Porphine (1, Chart 1) is the simplest porphyrin and represents the coremacrocycle of naturally occurring and synthetic porphyrins. Accordingly,porphine has been the subject of various experimental and theoreticalstudies as a benchmark compound in porphyrin chemistry.¹ Due to thepresence of 8 open β-pyrrole sites and 4 meso sites, porphine is apotential building block for the elaboration of porphyrin derivatives.In this regard, porphine undergoes selective mono-bromination at aβ-position to give 2-bromoporphine, whereas the zinc chelate (Zn-1)undergoes reaction at a meso-position to give zinc(II) 5-bromoporphine.³On the other hand, Shi and Wheelhouse showed that the magnesium(II)chelate of porphine (Mg-1) undergoes tetrabromination to givemagnesium(II) meso-tetrabromoporphine.

Subsequent palladium-coupling reactions afforded the correspondingtetraaryl A₄-porphyrins, which included target porphyrins that are noteasily available by other routes (e.g., with heterocyclicsubstituents).² Senge has shown that porphine reacts with organolithiumreagents to provide meso-substituted A- or cis-A₂-porphyrins, which alsoare difficult to synthesize by other routes.⁴ In addition, the ironcomplex of porphine was studied as a simple model of myoglobin.⁵ Thesereports provide a glimmer of the possible synthetic utility of porphine;however, the practical use of porphine in synthetic chemistry andbiochemistry has been thwarted by two vexing and somewhat interrelatedlimitations: (1) lack of an efficient method of synthesis of porphine,and (2) extremely low solubility of the free base porphine.

The reported methods for the synthesis of porphine over the past 70years are summarized in Table 1. Fischer and Gleim obtained 17 mg ofporphine by prolonged heating of 20 g of pyrrole-2-carboxaldehyde informic acid.⁶ In the same era, Rothemund obtained porphine from pyrroleand formaldehyde, albeit in very low yield (0.02%).⁷ The yield wasincreased to 0.9% by slow addition of pyrrole and formaldehyde topropionic acid.⁸

A significant improvement was achieved by the use of2-hydroxymethylpyrrole. Krol increased the yield of porphine up to 5%using 2-hydroxymethylpyrrole in glacial acetic acid containing acatalytic amount of magnesium acetate and potassium persulfate as anoxidizing reagent.⁹ Other improvements were reported by Adler and Longo(addition of hydroxymethylpyrrole periodically over several days withethylbenzene as solvent,)¹⁰ and by Yalman (use of DMF as a solvent andmetal salts afforded porphine in 20%,¹¹ although this yield hassubsequently been claimed to be non-reproducible¹²). Recently, Ellisprepared porphine in a biphasic system in 15.3% yield.¹² The use of1-hydroxypyrrole under micellar conditions afforded porphine in ˜2%yield.¹³

In a related approach, N,N-dimethylaminomethylpyrrole has been utilizedas a starting material. Copper(II) porphine was prepared fromN,N-dimethylaminomethylpyrrole in two steps.¹⁴ First, refluxingN,N-dimethylaminomethylpyrrole in chlorobenzene in the presence ofethylmagnesium bromide provided 2,3-dihydroporphine (chlorin) in 3.86%yield. The chlorin was quantitatively converted to copper(II) porphineby heating in acetic acid in the presence of copper(II) acetate.Formation of nickel(II) porphine was also observed as a byproduct in thesynthesis of chlorin by simply heating N,N-dimethylaminomethylpyrrole inpyridine in the presence of nickel(II) acetate (yield was notreported).¹⁵

Currently, the most popular method for preparing porphine entails thedealkylation of tetrakis(tert-butylporphyrin) in the presence of strongacid.^(16,17) The tert-butyl groups can be located at meso- orβ-positions. The yield of porphine upon dealkylation ofmeso-tetra(tert-butyl)porphine is 64-74%; however, this method requiresthe initial preparation of meso-tetra(tert-butyl)porphine. Porphine alsocan be prepared by the condensation of tripyrrin with2,5-bis(hydroxymethyl)pyrrole and subsequent oxidation of the resultingporphyrinogen by p-chloranil in 31% yield.¹⁸

Despite the structural simplicity of porphine, there remains no methodof satisfactory yield, scale, and ease of implementation that enablesthe synthetic capabilities of porphine to be unlocked. The majordrawbacks of the existing routes are: (1) low yields of macrocycleformation, which can be compensated in some cases by the use of easilyavailable starting materials (e.g., pyrrole and formaldehyde); (2) lowconcentration reactions; (3) long reaction times; (4) tedious separationof porphine from the large amount of polymeric material in the crudereaction mixture; and/or (5) lengthy synthetic paths (e.g., five stepsfrom commercially available starting material).

SUMMARY OF THE INVENTION

A first aspect of the invention is a method of making a compound ofFormula I:

comprising: condensing (i) a pair of compounds of Formula II:

with (ii) a metal salt under basic conditions to produce said compoundof Formula I.

A second aspect of the invention is a method of making a compound ofFormula I:

comprising condensing (i) a compound of Formula III with a compoundFormula IV

with (ii) a metal salt under basic conditions to produce the compound ofFormula I.

Groups “A”, “B”, “R”, and “X” are as discussed in greater detail below.

The foregoing and other objects and aspects of the present invention areexplained in greater detail in the specification set forth below.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS A. Definitions

“Halo” as used herein refers to any suitable halogen, including —F, —Cl,—Br, and —I.

“Mercapto” as used herein refers to an —SH group.

“Azido” as used herein refers to an —N₃ group.

“Cyano” as used herein refers to a —CN group.

“Hydroxyl” as used herein refers to an —OH group.

“Nitro” as used herein refers to an —NO₂ group.

“Alkyl” as used herein alone or as part of another group, refers to astraight or branched chain hydrocarbon containing from 1 or 2 to 10, 20or 50 carbon atoms (e.g., C1 to C4 alkyl; C4 to C10 alkyl; C11 to C50alkyl). Representative examples of alkyl include, but are not limitedto, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl,n-decyl, and the like. “Loweralkyl” as used herein, is a subset ofalkyl, in some embodiments preferred, and refers to a straight orbranched chain hydrocarbon group containing from 1 to 4 carbon atoms.Representative examples of loweralkyl include, but are not limited to,methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, andthe like. The term “alkyl” or “loweralkyl” is intended to include bothsubstituted and unsubstituted alkyl or loweralkyl unless otherwiseindicated and these groups may be substituted with groups selected fromhalo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,aryl, arylalkyl, heterocyclo, heterocycloalkyl, hydroxyl, alkoxy,alkenyloxy, alkynyloxy, haloalkoxy, cycloalkoxy, cycloalkylalkyloxy,aryloxy, arylalkyloxy, heterocyclooxy, heterocycloalkyloxy, mercapto,alkyl-S(O)_(m), haloalkyl-S(O)_(m), alkenyl-S(O)_(m), alkynyl-S(O)_(m),cycloalkyl-S(O)_(m), cycloalkylalkyl-S(O)_(m), aryl-S(O)_(m),arylalkyl-S(O)_(m), heterocyclo-S(O)_(m), heterocycloalkyl-S(O)_(m),amino, carboxy, alkylamino, alkenylamino, alkynylamino, haloalkylamino,cycloalkylamino, cycloalkylalkylamino, arylamino, arylalkylamino,heterocycloamino, heterocycloalkylamino, disubstituted-amino, acylamino,acyloxy, ester, amide, sulfonamide, urea, alkoxyacylamino, aminoacyloxy,nitro or cyano where m=0, 1, 2 or 3.

“Alkylene” as used herein refers to a difunctional linear, branched orcyclic alkyl group, which may be substituted or unsubstituted, and where“alkyl” is as defined above.

“Alkenyl” as used herein alone or as part of another group, refers to astraight or branched chain hydrocarbon containing from 1 or 2 to 10, 20or 50 carbon atoms (e.g., C1 to C4 alkenyl; C4 to C10 alkenyl; C11 toC50 alkenyl) (or in loweralkenyl 1 to 4 carbon atoms) which include 1 to4 double bonds in the normal chain. Representative examples of alkenylinclude, but are not limited to, vinyl, 2-propenyl, 3-butenyl,2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl,2,4-heptadienyl, and the like. The term “alkenyl” or “loweralkenyl” isintended to include both substituted and unsubstituted alkenyl orloweralkenyl unless otherwise indicated and these groups may besubstituted with groups as described in connection with alkyl andloweralkyl above.

“Alkenylene” as used herein refers to a difunctional linear, branched orcyclic alkyl group, which may be substituted or unsubstituted, and where“alkenyl” is as defined above.

“Alkynyl” as used herein alone or as part of another group, refers to astraight or branched chain hydrocarbon containing from 1 or 20 to 10, 20or 50 carbon atoms (e.g., C1 to C4 alkynyl; C4 to C10 alkynyl; C11 toC50 alkynyl) (or in loweralkynyl 1 to 4 carbon atoms) which include 1triple bond in the normal chain. Representative examples of alkynylinclude, but are not limited to, 2-propynyl, 3-butynyl, 2-butynyl,4-pentynyl, 3-pentynyl, and the like. The term “alkynyl” or“loweralkynyl” is intended to include both substituted and unsubstitutedalkynyl or loweralknynyl unless otherwise indicated and these groups maybe substituted with the same groups as set forth in connection withalkyl and loweralkyl above.

“Alkynylene” as used herein refers to a difunctional linear, branched orcyclic alkynyl group, which may be substituted or unsubstituted, andwhere “alkynyl” is as defined above.

“Alkylidene chain” as used herein refers to a difunctional linear,branched, and/or cyclic organic group, which may be substituted orunsubstituted, which may be saturated or unsaturated, and which mayoptionally contain one, two or three heteroatoms selected from the groupconsisting of N, O, and S. Examples include but are not limited toalkylene, alkenylene, alkynylene, arylene, alkarylene, and aralkylene.See, e.g., U.S. Pat. No. 6,946,533. The alkylidene chain may contain anysuitable number of carbon atoms (e.g., a C1 to C4; C4 to C10; C10 toC20; C20 to C50).

“Alkoxy” as used herein alone or as part of another group, refers to analkyl or loweralkyl group, as defined herein, appended to the parentmolecular moiety through an oxy group, —O—. Representative examples ofalkoxy include, but are not limited to, methoxy, ethoxy, propoxy,2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy and the like.

“Acyl” as used herein alone or as part of another group, refers to a—C(O)R radical, where R is any suitable substituent such as H, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl,cycloalkylalkynyl, heterocyclo, heterocycloalkyl, heterocycloalkenyl,heterocycloalkynyl, acetal, aryl, aryloxy, arylalkyl, arylalkenyl,arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl,heteroarylalkynyl, alkoxy, halo, mercapto, azido, cyano, acyl, formyl,carboxylic acid, acylamino, ester, amide, hydroxyl, nitro, alkylthio,amino, alkylamino, arylalkylamino, disubstituted amino, acyloxy,sulfoxyl, sulfonyl, sulfonate, sulfonic acid, sulfonamide, urea,alkoxylacylamino, aminoacyloxy, linking groups, surface attachmentgroups, bioconjugatable groups, targeting groups, or a water solublegroup.

“Haloalkyl” as used herein alone or as part of another group, refers toat least one halogen, as defined herein, appended to the parentmolecular moiety through an alkyl group, as defined herein.Representative examples of haloalkyl include, but are not limited to,chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl,2-chloro-3-fluoropentyl, and the like.

“Alkylthio” as used herein alone or as part of another group, refers toan alkyl group, as defined herein, appended to the parent molecularmoiety through a thio moiety, as defined herein. Representative examplesof alkylthio include, but are not limited to, methylthio, ethylthio,tert-butylthio, hexylthio, and the like.

“Aryl” as used herein alone or as part of another group, refers to amonocyclic carbocyclic ring system or a bicyclic carbocyclic fused ringsystem having one or more aromatic rings. Representative examples ofaryl include, azulenyl, indanyl, indenyl, naphthyl, phenyl,tetrahydronaphthyl, and the like. The term “aryl” is intended to includeboth substituted and unsubstituted aryl unless otherwise indicated andthese groups may be substituted with the same groups as set forth inconnection with alkyl and loweralkyl above.

“Arylalkyl” as used herein alone or as part of another group, refers toan aryl group, as defined herein, appended to the parent molecularmoiety through an alkyl group, as defined herein. Representativeexamples of arylalkyl include, but are not limited to, benzyl,2-phenylethyl, 3-phenylpropyl, 2-naphth-2-ylethyl, and the like.

“Amino” as used herein means the radical —NH₂.

“Alkylamino” as used herein alone or as part of another group means theradical —NHR, where R is an alkyl group.

“Arylalkylamino” as used herein alone or as part of another group meansthe radical —NHR, where R is an arylalkyl group.

“Disubstituted-amino” as used herein alone or as part of another groupmeans the radical —NR_(a)R_(b), where R_(a) and R_(b) are independentlyselected from the groups alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl.

“Acylamino” as used herein alone or as part of another group means theradical —NR_(a)R_(b), where R_(a) is an acyl group as defined herein andR_(b) is selected from the groups hydrogen, alkyl, haloalkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo,heterocycloalkyl.

“Acyloxy” as used herein alone or as part of another group means theradical —OR, where R is an acyl group as defined herein.

“Ester” as used herein alone or as part of another group refers to a—C(O)OR radical,

where R is any suitable substituent such as alkyl, cycloalkyl, alkenyl,alkynyl or aryl.

“Formyl” as used herein refers to a —C(O)H group.

“Carboxylic acid” as used herein refers to a —C(O)OH group.

“Sulfoxyl” as used herein refers to a compound of the formula —S(O)R,where R is any suitable substituent such as alkyl, cycloalkyl, alkenyl,alkynyl or aryl.

“Sulfonyl” as used herein refers to a compound of the formula —S(O)(O)R,where R is any suitable substituent such as alkyl, cycloalkyl, alkenyl,alkynyl or aryl.

“Sulfonate” as used herein refers to a compound of the formula—S(O)(O)OR, where R is any suitable substituent such as alkyl,cycloalkyl, alkenyl, alkynyl or aryl.

“Sulfonic acid” as used herein refers to a compound of the formula—S(O)(O)OH.

“Amide” as used herein alone or as part of another group refers to a—C(O)NR_(a)R_(b) radical, where R_(a) and R_(b) are any suitablesubstituent such as H, alkyl, cycloalkyl, alkenyl, alkynyl or aryl.

“Sulfonamide” as used herein alone or as part of another group refers toa —S(O)₂NR_(a)R_(b) radical, where R_(a) and R_(b) are any suitablesubstituent such as H, alkyl, cycloalkyl, alkenyl, alkynyl or aryl.

“Urea” as used herein alone or as part of another group refers to an—N(R_(c))C(O)NR_(a)R_(b) radical, where R_(a), R_(b) and R_(c) are anysuitable substituent such as H, alkyl, cycloalkyl, alkenyl, alkynyl oraryl.

“Alkoxyacylamino” as used herein alone or as part of another grouprefers to an —N(R_(a))C(O)OR_(b) radical, where R_(a), R_(b) are anysuitable substituent such as H, alkyl, cycloalkyl, alkenyl, alkynyl oraryl.

“Aminoacyloxy” as used herein alone or as part of another group refersto an —OC(O)NR_(a)R_(b) radical, where R_(a) and R_(b) are any suitablesubstituent such as H, alkyl, cycloalkyl, alkenyl, alkynyl or aryl.

“Cycloalkyl” as used herein alone or as part of another group, refers toa saturated or partially unsaturated cyclic hydrocarbon group containingfrom 3, 4 or 5 to 6, 7 or 8 carbons (which carbons may be replaced in aheterocyclic group as discussed below). Representative examples ofcycloalkyl include, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl. These rings may be optionally substitutedwith additional substituents as described herein such as halo orloweralkyl. The term “cycloalkyl” is generic and intended to includeheterocyclic groups as discussed below unless specified otherwise.

“Heterocyclic group” or “heterocyclo” as used herein alone or as part ofanother group, refers to an aliphatic (e.g., fully or partiallysaturated heterocyclo) or aromatic (e.g., heteroaryl) monocyclic- or abicyclic-ring system. Monocyclic ring systems are exemplified by any 5or 6 membered ring containing 1, 2, 3, or 4 heteroatoms independentlyselected from oxygen, nitrogen and sulfur. The 5 membered ring has from0-2 double bonds and the 6 membered ring has from 0-3 double bonds.Representative examples of monocyclic ring systems include, but are notlimited to, azetidine, azepine, aziridine, diazepine, 1,3-dioxolane,dioxane, dithiane, furan, imidazole, imidazoline, imidazolidine,isothiazole, isothiazoline, isothiazolidine, isoxazole, isoxazoline,isoxazolidine, morpholine, oxadiazole, oxadiazoline, oxadiazolidine,oxazole, oxazoline, oxazolidine, piperazine, piperidine, pyran,pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridine, pyrimidine,pyridazine, pyrrole, pyrroline, pyrrolidine, tetrahydrofuran,tetrahydrothiophene, tetrazine, tetrazole, thiadiazole, thiadiazoline,thiadiazolidine, thiazole, thiazoline, thiazolidine, thiophene,thiomorpholine, thiomorpholine sulfone, thiopyran, triazine, triazole,trithiane, and the like. Bicyclic ring systems are exemplified by any ofthe above monocyclic ring systems fused to an aryl group as definedherein, a cycloalkyl group as defined herein, or another monocyclic ringsystem as defined herein. Representative examples of bicyclic ringsystems include but are not limited to, for example, benzimidazole,benzothiazole, benzothiadiazole, benzothiophene, benzoxadiazole,benzoxazole, benzofuran, benzopyran, benzothiopyran, benzodioxine,1,3-benzodioxole, cinnoline, indazole, indole, indoline, indolizine,naphthyridine, isobenzofuran, isobenzothiophene, isoindole, isoindoline,isoquinoline, phthalazine, purine, pyranopyridine, quinoline,quinolizine, quinoxaline, quinazoline, tetrahydroisoquinoline,tetrahydroquinoline, thiopyranopyridine, and the like. These ringsinclude quaternized derivatives thereof and may be optionallysubstituted with groups selected from halo, alkyl, haloalkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo,heterocycloalkyl, hydroxyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy,cycloalkoxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy,heterocycloalkyloxy, mercapto, alkyl-S(O)_(m), haloalkyl-S(O)_(m),alkenyl-S(O)_(m), alkynyl-S(O)_(m), cycloalkyl-S(O)_(m),cycloalkylalkyl-S(O)_(m), aryl-S(O)_(m), arylalkyl-S(O)_(m),heterocyclo-S(O)_(m), heterocycloalkyl-S(O)_(m), amino, alkylamino,alkenylamino, alkynylamino, haloalkylamino, cycloalkylamino,cycloalkylalkylamino, arylamino, arylalkylamino, heterocycloamino,heterocycloalkylamino, disubstituted-amino, acylamino, acyloxy, ester,amide, sulfonamide, urea, alkoxyacylamino, aminoacyloxy, nitro or cyanowhere m=0, 1, 2 or 3. Preferred heterocyclo groups include pyridyl andimidazolyl groups, these terms including the quaternized derivativesthereof, including but not limited to quaternary pyridyl and imidazolylgroups, examples of which include but are not limited to:

where R and R′ are each a suitable substituent as described inconnection with “alkyl” above, and particularly alkyl (such as methyl,ethyl or propyl), arylalkyl (such as benzyl), optionally substitutedwith hydroxy (—OH), phosphonic acid (—PO₃H₂) or sulfonic acid (—SO₃H),and X⁻ is a counterion.

“Spiroalkyl” as used herein alone or as part of another group, refers toa straight or branched chain hydrocarbon, saturated or unsaturated,containing from 3 to 8 carbon atoms. Representative examples include,but are not limited to, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂CH₂—,—CH₂CH₂CHCHCH₂—, —CH₂CH₂CH₂CH₂CH₂CH₂—, etc. The term “spiroalkyl” isintended to include both substituted and unsubstituted “spiroalkyl”unless otherwise indicated and these groups may be substituted withgroups selected from halo, alkyl, haloalkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo,heterocycloalkyl, hydroxyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy,cycloalkoxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy,heterocycloalkyloxy, mercapto, alkyl-S(O)_(m), haloalkyl-S(O)_(m),alkenyl-S(O)_(m), alkynyl-S(O)_(m), cycloalkyl-S(O)_(m),cycloalkylalkyl-S(O)_(m), aryl-S(O)_(m), arylalkyl-S(O)_(m),heterocyclo-S(O)_(m), heterocycloalkyl-S(O)_(m), amino, alkylamino,alkenylamino, alkynylamino, haloalkylamino, cycloalkylamino,cycloalkylalkylamino, arylamino, arylalkylamino, heterocycloamino,heterocycloalkylamino, disubstituted-amino, acylamino, acyloxy, ester,amide, sulfonamide, urea, alkoxyacylamino, aminoacyloxy, nitro or cyanowhere m=0, 1 or 2.

“Aldehyde” as used herein refers to a group of the formula:

“Acetal” as used herein refers to a group of the formula:

where R and R′ are each suitable groups, e.g., groups independentlyselected from the group consisting of alkyl, aryl, alkylaryl, or where Rand R′ together form a group —R″— where R″ is an alkylene (i.e.,cycloalkyl). The acetal is preferably reasonably robust, and hence it ispreferred that at least one, or more preferably both, of R and R′ is notmethyl, and it is particularly preferred that neither R nor R′ is H.

“Macrocyclic ligand” as used herein means a macrocyclic molecule ofrepeating units of carbon atoms and hetero atoms (e.g., O, S, or NH),separated by the carbon atoms (generally by at least two or three carbonatoms). Macrocyclic ligands exhibit a conformation with a so-called holecapable of trapping ions or molecules, particularly cations, bycoordination with the electrons of the hetero atom (e.g., a lone pair ofelectrons on the oxygen atoms when the hetero atoms are oxygen). Ingeneral, the macrocyclic ring contains at least 9, 12 or 14 carbon atomsand hetero atoms (e.g., O, S, NH), each hetero atom in the ring beingseparated from adjoining hetero atoms in the ring by two or more carbonatoms. The macrocyclic ring may be substituted or unsubstituted, and maybe fused to additional rings (e.g., 1 to 4 additional rings such asphenylene, naphthylene, phenanthrylene, and anthrylene rings). Themacrocyclic ligand may be in the form of a substituent. See, e.g., U.S.Pat. No. 6,411,164 to Sibert.

“Polar group” as used herein refers to a group wherein the nuclei of theatoms covalently bound to each other to form the group do not share theelectrons of the covalent bond(s) joining them equally; that is theelectron cloud is denser about one atom than another. This results inone end of the covalent bond(s) being relatively negative and the otherend relatively positive; i.e., there is a negative pole and a positivepole. Examples of polar groups include, without limitations, hydroxy,alkoxy, carboxy, nitro, cyano, amino (primary, secondary and tertiary),amido, ureido, sulfonamido, sulfinyl, sulfhydryl, silyl, S-sulfonamido,N-sulfonamido, C-carboxy, O-carboxy, C-amido, N-amido, sulfonyl,phosphono, morpholino, piperazinyl, tetrazolo, and the like. See, e.g.,U.S. Pat. No. 6,878,733, as well as alcohol, thiol, polyethylene glycol,polyol (including sugar, aminosugar, uronic acid), sulfonamide,carboxamide, hydrazide, N-hydroxycarboxamide, urea, metal chelates(including macrocyclic ligand or crown ether metal chelates)

“Ionic group” as used herein includes anionic and cationic groups, andincludes groups (sometimes referred to as “ionogenic” groups) that areuncharged in one form but can be be easily converted to ionic groups(for example, by protonation or deprotonation in aqueous solution).Examples include but are not limited to carboxylate, sulfonate,phosphate, amine, N-oxide, and ammonium (including quaternizedheterocyclic amines such as imidazolium and pyridinium as describedabove) groups. See, e.g., U.S. Pat. Nos. 6,478,863; 6,800,276; and6,896,246. Additional examples include uronic acids, carboxylic acid,sulfonic acid, amine, and moieties such as guanidinium, phosphoric acid,phosphonic acid, phosphatidyl choline, phosphonium, borate, sulfate,etc. Note that compounds of the present invention can contain both ananionic group as one ionic substituent and a cationic group as anotherionic substituent, with the compounds hence being zwitterionic. Notealso that the compounds of the invention can contain more than oneanionic or more than one cationic group.

“Protecting group” as used herein includes any suitable protectinggroup; “protected form” refers to a substituent in which an atom such ashydrogen has been removed and replaced with a corresponding protectinggroup. Protecting groups are known. See generally T. H. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley& Sons, New York (1999). Examples include but are not limited to:hydroxy protecting groups (for producing the protected form of hydroxy);carboxy protecting groups (for producing the protected form ofcarboxylic acid); amino-protecting groups (for producing the protectedform of amino); sulfhydryl protecting groups (for producing theprotected form of sulfhydryl); etc. Particular examples include but arenot limited to: benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, methoxycarbonyl,tert-butoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl,2-furfuryloxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl,trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl,2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, 1,1-dimethyl-2-propenyl,3-methyl-3-butenyl, allyl, benzyl, para-methoxybenzyldiphenylmethyl,triphenylmethyl (trityl), tetrahydrofuryl, methoxymethyl,methylthiomethyl, benzyloxymethyl, 2,2,2-triehloroethoxymethyl,2-(trimethylsilyl)ethoxymethyl, methanesulfonyl, para-toluenesulfonyl,trimethylsilyl, triethylsilyl, triisopropylsilyl, acetyl (Ac or—C(O)CH₃), benzoyl (Bn or —C(O)C₆H₅), and trimethylsilyl (TMS or—Si(CH₃)₃), and the like; formyl, acetyl, benzoyl, pivaloyl,t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), andbenzyloxycarbonyl (Cbz) and the like; and hemithioacetals such as1-ethoxyethyl and methoxymethyl, thioesters, or thiocarbonates and thelike. See, e.g., U.S. Pat. Nos. 6,953,782; 6,951,946; 6,951,942; and6,051,724. Particularly preferred are halo, thio (e.g., alkylthio,thiocyanate), acetate, sulfonate, and triflate protecting groups.

“Antibody” as used herein refers generally to immunoglobulins orfragments thereof that specifically bind to antigens to form immunecomplexes. The antibody may be whole immunoglobulin of any class, e.g.,IgG, IgM, IgA, IgD, IgE, chimeric or hybrid antibodies with dual ormultiple antigen or epitope specificities. It can be a polyclonalantibody, preferably an affinity-purified antibody from a human or anappropriate animal, e.g., a primate, goat, rabbit, mouse or the like.Monoclonal antibodies are also suitable for use in the presentinvention, and are preferred because of their high specificities. Theyare readily prepared by what are now considered conventional proceduresof immunization of mammals with immunogenic antigen preparation, fusionof immune lymph or spleen cells with an immortal myeloma cell line, andisolation of specific hybridoma clones. More unconventional methods ofpreparing monoclonal antibodies are not excluded, such as interspeciesfusions and genetic engineering manipulations of hypervariable regions,since it is primarily the antigen specificity of the antibodies thataffects their utility. Newer techniques for production of monoclonalscan also be used, e.g., human monoclonals, interspecies monoclonals,chimeric (e.g., human/mouse) monoclonals, genetically engineeredantibodies and the like.

“Coupling agent” as used herein, refers to a reagent capable of couplinga photosensitizer to a targeting agent

“Targeting agent” refers to a compound that homes in on orpreferentially associates or binds to a particular tissue, receptor,infecting agent or other area of the body of the subject to be treated,such as a target tissue or target composition. Examples of a targetingagent include but are not limited to an antibody, a ligand, one memberof a ligand-receptor binding pair, nucleic acids, proteins and peptides,and liposomal suspensions, including tissue-targeted liposomes.

“Specific binding pair” and “ligand-receptor binding pair” as usedherein refers to two different molecules, where one of the molecules hasan area on the surface or in a cavity which specifically attracts orbinds to a particular spatial or polar organization of the othermolecule, causing both molecules to have an affinity for each other. Themembers of the specific binding pair are referred to as ligand andreceptor (anti-ligand). The terms ligand and receptor are intended toencompass the entire ligand or receptor or portions thereof sufficientfor binding to occur between the ligand and the receptor. Examples ofligand-receptor binding pairs include, but are not limited to, hormonesand hormone receptors, for example epidermal growth factor and epidermalgrowth factor receptor, tumor necrosis factor-alpha and tumor necrosisfactor-receptor, and interferon and interferon receptor; avidin andbiotin or antibiotin; antibody and antigen pairs; enzymes andsubstrates, drug and drug receptor; cell-surface antigen and lectin; twocomplementary nucleic acid strands; nucleic acid strands andcomplementary oligonucleotides; interleukin and interleukin receptor;and stimulating factors and their receptors, such asgranulocyte-macrophage colony stimulating factor (GMCSF) and GMCSFreceptor and macrophage colony stimulating factor (MCSF) and MCSFreceptor.

“Linkers”, or “linker groups” are aromatic or aliphatic groups (whichmay be substituted or unsubstituted and may optionally containheteroatoms such as N, O, or S) that are utilized to couple abioconjugatable group, cross-coupling group, surface attachment group,hydrophilic group or the like to the parent molecule. Examples includebut are not limited to aryl, alkyl, heteroaryl, heteroalkyl (e.g.,oligoethylene glycol), peptide, and polysaccharide linkers, etc.

“Water soluble group” (or “water solubilizing group”) as used hereingenerally includes substituents containing at least one ionic or polargroup, coupled to the parent molecule directly or by means of anintervening linker. Examples include but are not limited to groups ofthe formula:

wherein R^(a) and R^(b) are each independently an ionic group or polargroup, and Alk^(a) and Alk^(b) are each independently a C1-C50alkylidene chain.

“Bronsted acid” as used herein refers to a molecular entity (andcorresponding chemical species) that is a proton donor to a base. Anysuitable Bronsted acid may be used as a catalyst, with examplesincluding but not limited to: trifluoroacetic acid, trichloroaceticacid, oxalic acid, taurine, malonic acid, formic acid, acetic acid, andNH₄Cl.

“Lewis acid” as used herein refers to a molecular entity (andcorresponding chemical species) that is an electron-pair acceptor andtherefore able to react with a Lewis base to form a Lewis adduct, bysharing the electron pair furnished by the Lewis base. Any suitableLewis acid may be used as a catalyst, examples including compounds ofthe general formula LnX₃ where Ln is a lanthanide and X is halo such asCl, Br, I, etc., triflate or OTf, etc., and with examples specificexamples including but not limited to: Yb(OTf)₃, InCl₃, Sc(OTf)₃, MgBr₂and CeCl₃.

B. Methods of Making Porphine and Porphyrins Including TransA₂B₂-porphyrins

As noted above, the present invention provides a method of making acompound of Formula I:

comprises condensing (i) a pair of compounds of Formula II:

with (ii) a metal salt under basic conditions to produce said compoundof Formula I.

In an alternate embodiment of the invention, a method of making acompound of Formula I as given above comprises condensing (i) a compoundof Formula III with a compound Formula IV

with (ii) a metal salt under basic conditions to produce the compound ofFormula I.

In each of the foregoing reactions, X is selected from the groupconsisting of O, S, Se, NH, NR, (OR)₂, (SR)₂, and (SeR)₂, wherein R isas given below, preferably alkyl or aryl.

In each of the foregoing reactions, each A is independently selectedfrom the group consisting of: H, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocyclo,heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, acetal, aryl,aryloxy, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl,heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, halo,mercapto, azido, cyano, acyl, formyl, carboxylic acid, acylamino, ester,amide, hydroxyl, nitro, alkylthio, amino, alkylamino, arylalkylamino,disubstituted amino, acyloxy, sulfoxyl, sulfonyl, sulfonate, sulfonicacid, sulfonamide, urea, alkoxylacylamino, aminoacyloxy, linking groups,surface attachment groups, bioconjugatable groups, targeting groups, andwater soluble groups.

In each of the foregoing reactions, each B is independently selectedfrom the group consisting of: H, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocyclo,heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, acetal, aryl,aryloxy, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl,heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, acyl,formyl, carboxylic acid, acylamino, alkylthio, amino, alkylamino,arylalkylamino, disubstituted amino, linking groups, surface attachmentgroups, bioconjugatable groups, targeting groups, and water solublegroups.

In each of the foregoing reactions, each R is independently selectedfrom the group consisting of: H, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocyclo,heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, acetal, aryl,aryloxy, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl,heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, halo,mercapto, azido, cyano, acyl, formyl, carboxylic acid, acylamino, ester,amide, hydroxyl, nitro, alkylthio, amino, alkylamino, arylalkylamino,disubstituted amino, acyloxy, sulfoxyl, sulfonyl, sulfonate, sulfonicacid, sulfonamide, urea, alkoxylacylamino, aminoacyloxy, linking groups,surface attachment groups, bioconjugatable groups, targeting groups, andwater soluble groups; or an adjacent pair of two R groups may togetherform an annulated arene or annulated alkene.

In some embodiments, the condensing step is preferably carried out in anon-coordinating solvent.

In some embodiments, the condensing step is preferably carried out inthe presence of a non-nucleophilic base.

It will be appreciated from the foregoing that, when all groups “A”,“B”, and “R” are hydrogen, the present invention provides a convenientmethod of making porphine by (i) self-condensing 1-formyl dipyrromethanein the presence of a metal salt under such basic conditions to produceporphine, (ii) by condensing 1,9-diformyldipyrromethane withdipyrromethane under such basic conditions to produce porphine, or (iii)by concurrently both condensing 1-formyl dipyrromethane with itselfwhile also condensing 1,9-diformyldipyrromethane with dipyrromethaneunder such basic conditions to produce porphine. Option (iii) above isadvantageous when dipyrromethane is formylated to produce a mixture ofdipyrromethane, 1-formyldipyrromethane, and 1,9-diformyldipyrromethane,as the mixture can then be used directly to make the metallatedporphine.

Any suitable metal salt can be used, depending on the metal desired inthe metalloporphyrin, with particular embodiments including but notlimited to magnesium, zinc, nickel and indium salt. In some embodiments,magnesium halides are particularly preferred.

Reaction conditions are not in all embodiments critical. In someembodiments the reaction is carried out under basic conditions (e.g.,with addition of a suitable base such as NaOH, ethylmagnesium bromide,2-mesityl magnesium bromide, 2,2,6,6-tetramethylpiperidine,tetramethylguanidine, etc) added to the reaction mixture). The reactionmay be solventless or may be carried out in a solvent. The solvent, ifused, is typically an organic solvent (including mixtures), examplesincluding ethanol, tetrahydrofuran (THF), valeronitrile,isovaleronitrile, butyronitrile, acetonitrile, xylene, mesitylene,chlorobenzene, dichlorobenzene, dichloromethane, chloroform, andtoluene. The choice of specific solvent will depend upon the choice ofmetal salt, with some metals such as magnesium requiring anon-coordinating solvent such as toluene or chlorobenzene. In somepreferred embodiments the reaction is carried out in a non-coordinatingor weakly coordinating (but not strongly coordinating) solvent such astoluene, xylene, 1,2-dichlorobenzene, dichloroethane, chlorobenzene,anisole (or methoxybenzene), etc., including mixtures thereof, in thepresence of a non-coordinating or mildly coordinating (but not stronglycoordinating) base such as 1,8-diazabicyclo[5.4.0]-undec-7-ene (or“DBU”), DBN, 2,2,6,6-tetramethylpiperidine, 2,6-di-tert-butylpyridine,etc., including mixtures thereof.

The reaction is formally carried out in the presence of an oxidant, suchas air (e.g., an open-atmosphere reaction without the inclusion of anadditional chemical oxidant beyond ambient oxygen), although neither airnor a tradition exogenous oxident appears essential as discussed below.The reaction may be carried for any suitable time (e.g., from one hourto two days) and at any temperature, including room temperature andelevated temperatures (e.g., from room temperature or 25° C., up to 70,100 or 200° C.), and/or with microwave irradiation, with any suitableconcentration of reactants (e.g., 10 or 20 up to 500 or 1000 mM, with100-200 mM currently preferred).

Once the porphyrin is formed, the metal can be displaced to form a freebase thereof. Displacement of the metal can be carried out by anysuitable technique, such as by displacement with an acid. See, e.g.,U.S. Pat. No. 6,946,552 to Lindsey et al.

Choice of starting materials (Compounds of Formula II). When the twomembers of the pair of 1-acyldipyrromethanes of Formula II that undergocondensation are identical, the resulting porphyrin can be of thetrans-A₂B₂ type wherein A≠B≠H. When A≠H and B=H, the resulting porphyrinis of the trans-A₂ type; alternatively, when A=H and B≠H, the resultingporphyrin again bears two substituents (derived from the B substituent)in a trans configuration. Again, such a porphyrin is referred to as atrans-A₂-porphyrin to indicate the presence of two meso substituents ina trans configuration.

When the two members of the pair of 1-acyldipyrromethanes that undergocondensation are not identical, the resulting reaction is statistical innature and yields as many as three porphyrin products. For a firstacyldipyrromethane bearing A/B substituents, and a secondacyldipyrromethane bearing C/D substituents, the resulting porphyrinsare the trans-A₂B₂-porphyrin, the trans-C₂D₂-porphyrin, and theABCD-porphyrin. The latter porphyrin is the so-called “hybrid” productgiven that it is derived from the two dipyrromethanes. This statisticalapproach is attractive when one wants access to the hybrid porphyrinwithout carrying out the larger number of steps typical of a rationalsynthesis. However, the statistical mixture of porphyrins typicallyrequires separation to obtain the target hybrid porphyrin.

Several non-limiting examples this hybrid approach are as follows:

(i) When C=D=H, and neither A nor B=H, the resulting porphyrins are thetrans-A₂B₂-porphyrin (from self-condensation of the AB-substituted1-acyldipyrromethane, the meso-unsubstituted porphyrin (derived from theCD-species, 1-formyldipyrromethane), and the hybrid porphyrin whichcontains a cis-AB substituent pattern. When C=D=H, and A=B, the hybridporphyrin contains a cis-A₂ substituent pattern (not shown). When C=D=H,and one of A or B but not both =H, the resulting hybrid porphyrincontains a single substituent (A-porphyrin) (not shown). Such sparselysubstituted porphyrins (cis-AB-, cis-A₂-, and A-porphyrins) are ofinterest for a number of applications as discussed in section C belowyet are difficult to access via rational routes.

(ii) When C=D≠H, and neither A nor B=H, the resulting porphyrins are thetrans-A₂B₂-porphyrin, the porphyrin with four identical substituents(derived from the C₂-substituted 1-acyldipyrromethane), and the hybridporphyrin which contains a cis-ABC₂ substituent pattern. When A=B, thehybrid porphyrin contains a cis-A₂C₂ substituent pattern. Suchcis-substituted porphyrins are of interest for a number of applicationsas discussed in section C below.

Again, a chief advantage of the statistical approach is that it providesa straightforward route to cis-substituted and/or sparsely substitutedporphyrins, among which include amphipathic architectures containingalkyl and/or heterocyclic groups.

C. Utility

Porphyrin compounds as described herein are useful for a variety ofpurposes, including but not limited to: as charge storage groups ininformation storage devices; as detectable groups in a variety ofdetection techniques; and as chromophores in solar cells, lightharvesting rods and light harvesting arrays; as discussed further below.

Information storage devices. Porphyrin compounds described herein areuseful immobilized to a substrate for making charge storage moleculesand information storage devices containing the same, either individuallyor as linked polymers thereof, either optionally including additionalcompounds to add additional oxidation states. Such charge storagemolecules and information storage devices are known and described in,for example, U.S. Pat. No. 6,208,553 to Gryko et al.; U.S. Pat. No.6,381,169 to Bocian et al.; and U.S. Pat. No. 6,324,091 to Gryko et al.The porphyrins of the invention may comprise a member of a sandwichcoordination compound in the information storage molecule, such asdescribed in U.S. Pat. No. 6,212,093 to Li et al. or U.S. Pat. No.6,451,942 to Li et al.

Detection techniques. Porphyrin compounds as described herein can bedetected by any suitable technique and hence used as detectable groupsin a variety of techniques, including but not limited to flow cytometry,fluorescence spectroscopy, with a multi-well fluorescent plate scanner,scanning cytometry, fluorescent or immunofluorescent microscopy, laserscanning cytometry, bright field base image analysis, capillaryvolumetry, manual cell analysis and automated cell analysis. See, e.g.,U.S. Pat. Nos. 5,314,805; 6,551,788 and 6,623,982.

Solar cells, light harvesting rods and light harvesting arrays.Porphyrin compounds described herein may be used as chromophores (alsoreferred to as photosensitizers or simply sensitizers) in solar cells,including but not limited to high surface area colloidal semiconductorfilm solar cells (Gratzel cells), as described in, for example, U.S.Pat. Nos. 5,441,827; 6,420,648; 6,933,436; 6,924,427; 6,913,713;6,900,382; 6,858,158; and 6,706,963. Compounds described herein may beused as chromophores in the light harvesting rods described in U.S. Pat.Nos. 6,407,330 and 6,420,648 (incorporated herein by reference). Thelight harvesting rod may comprise one or more porphyrin compound coupledto one or two adjacent chromophores depending upon the position thereofin the light harvesting rod. Such light harvesting rods may be utilizedto produce light harvesting arrays as described in U.S. Pat. No.6,420,648 and solar cells as described in U.S. Pat. No. 6,407,330.

The present invention is explained in greater detail in the followingexperimental section set forth below, which is to be construed asillustrative and not limiting of the invention.

Experimental

Here we report an efficient, concise, and practical method for preparingmagnesium(II) porphine, which greatly facilitates access to thisvaluable compound, and from which free base porphine is readilyobtained.

Results and Discussion

I. Strategy. Our approach for the synthesis of porphine has emerged fromour prior studies of routes to trans-substituted porphyrins. The keymethods are as follows:

(i) The self-condensation of a dipyrromethane-1-carbinol in the presenceof a Lewis acid^(19,20) affords the trans-A₂B₂ porphyrin. However, theuse of this method for the synthesis of porphine suffers from two majordrawbacks, low reactivity of hydroxymethyldipyrromethane (1° carbinol)in the acid-catalyzed self-condensation process and lack of an efficientsynthetic route to 1-formyldipyrromethane (the most viable precursor forcorresponding 1-hydroxymethyldipyrromethane).

(ii) The self-condensation of a 1-acyldipyrromethane in refluxingethanol containing KOH and a palladium reagent affords the correspondingpalladium(II) chelate of a trans-A₂B₂-porphyrin.²²

(iii) The reaction of 1,9-diformyldipyrromethane with n-propylamine andsubsequent reaction of the bis(imino)dipyrromethane with adipyrromethane in the presence of Zn(OAc)₂ in the refluxing ethanolexposed to air affords the zinc(II) complex of the trans-AB-porphyrin.²³However, application of this method with the unsubstituteddipyrromethane usually resulted in little or no porphyrin.²³

(iv) As part of our work in chlorin chemistry, we recently developed anefficient route for the synthesis of 1-formyldipyrromethanes.²¹ Theformylation method entailed traditional Vilsmeier formylation ortreatment of a solution of dipyrromethane in THF at room temperaturewith 2 molar equiv of MesMgBr and then at −78° C. with 2 molar equiv ofphenyl formate. The subsequent workup and column chromatography affordedthe desired 1-formyldipyrromethane in good yields.

Given the aforementioned developments in porphyrin and dipyrromethanechemistry, and taking into consideration the limitation of existingsynthetic methods to porphine in particular and porphyrins in general,we chose 1-formyldipyrromethane 2 as a potentially viable precursor toporphine. The conditions examined are described in the next section.

2. Survey of Approaches. Three approaches for the self-condensation of 2have been examined (Scheme 1). Each approach should afford direct accessto the metalloporphine M-1, thereby sidestepping the difficultpurification and handling problems of the poorly soluble free baseporphine.

A. Formation of Palladium(II) porphine. Reaction of 2 in the presence ofa palladium(II) salt under basic conditions in refluxing ethanol[Pd(CH₃CN)₂Cl₂ in EtOH containing KOH]²² afforded palladium(II) porphine(Pd-1) in 11% yield. Palladium(II) porphine was easily purified byfiltration through a silica pad.

B. Formation of Zinc(II) porphine. Reaction of 2 with excessn-propylamine in THF at room temperature (conditions used previouslywith 1,9-diformyldipyrromethanes to form the bis-imine)²³ affordedquantitatively the corresponding imine. The self-condensation of theresulting imine in refluxing EtOH containing Zn(OAc)₂ afforded Zn(II)porphine (Zn-1) in 13% yield (yield of isolated porphine determined byabsorption spectrometry). Note that due to the symmetrical nature ofporphine, any scrambling by the traditional acid-catalyzed pathways isirrelevant.

C. Formation of Magnesium(II) porphine. A lengthy study was carried outto explore the generality of the basic, metal-templated conditions forthe self-condensation of 1-acyldipyrromethanes. Such conditions employedPd(CH₃CN)₂Cl₂ in EtOH containing KOH. The study, which encompasseddifferent metals, solvents, and bases, will be reported elsewhere. Onekey finding is that a Mg(II) salt (e.g., MgBr₂) in the presence of anon-nucleophilic base (e.g., DBU) provides an effective means for theself-condensation of 1-acyldipyrromethanes. The concept leading to theuse of MgBr₂ and DBU stemmed from our study on the magnesium insertioninto porphyrin, wherein similar conditions in the absence of anyoxygenic ligands afford the magnesium(II) porphyrin under mildconditions.²⁴ For the reaction of 2, the formyl group should beactivated by coordination to magnesium(II) given the high affinity ofmagnesium(II) for oxygen. The choice of non-coordinated solvent andnon-nucleophilic base is critical to avoid any competition between thesolvent and base and the 1-formyldipyrromethane in coordination tomagnesium.

Thus, refluxing a mixture of 2 (100 mM) in toluene containing DBU (10equiv vs. 2) and MgBr₂ (3 equiv) in the presence of air afforded Mg(II)porphine (Mg-1) in 41% yield. Note that no quinone oxidant is required.Mg(II) porphine was purified by filtration through an alumina column. Nofree base porphine was detected in the reaction mixture. The TLCanalysis of crude reaction mixture revealed the presence of only Mg-1and highly polar, polymeric material. Neither starting material normacrocyclic byproducts were detected. Therefore we performed thepurification of Mg-1 without column chromatography. The crude reactionmixture was concentrated. The resulting oily material was treated withTHF, filtered (to remove the polymeric material and inorganic salt), andfiltrate was concentrated. Subsequent washing with water (to remove anexcess of DBU) and crystallization from ethanol/water afforded Mg-1 insatisfactory purity. Mg-1 is stable in solution but undergoes partialdecomplexation upon silica column chromatography; fortunately, Mg-1 canbe purified by crystallization and no chromatography is required. Notethat Mg(II) porphine (Mg-1) was previously prepared by metalation of 1.²

The overall stoichiometry for the reaction is shown in Scheme 2. Thestoichiometry shows the requirement for a base and an oxidant. The baseis required, minimally, to neutralize the two equivalents of HBrliberated upon metal complexation. In this regard, the conditions ofMgBr₂ and a non-nucleophilic base resemble those for magnesium insertioninto free base porphyrins.²⁴ A 2e−/2H+ oxidant is formally required toform the unsaturated macrocycle. Oxygen present in air would seem alikely source for the oxidizing equivalents. However, the microwavereaction in a degassed flask gave Mg-1 in essentially identical yield tothat carried out in an aerobic environment. The essential requirementfor both MgBr₂ and DBU was validated by omission experiments, where thereaction of 2 carried out in the absence of either DBU or MgBr₂ gave noporphine.

The condensation of 1,9-diformyldipyrromethane with dipyrromethane underanalogous conditions afforded Mg-1 albeit in lower yield (18%, Scheme3).

3. Scalable Synthesis of Mg-1. The high yield and the operationalsimplicity of Mg-1 formation prompted examination of the reaction atmultigram scale. Thus, self-condensation of 6.97 g of 2 afforded 2.68 gof Mg-1 in a single batch process. Although the porphine-formingreaction afforded a crude product that could be purified bycrystallization (and no chromatography), the synthesis of the precursorsrequired chromatography thereby limiting the scale of reaction.

1-Formyldipyrromethane 2 is the key precursor for the porphine synthesisdescribed herein. Formylation of dipyrromethane via Vilsmeier orGrignard reagent mediated syntheses²¹ results in multiple byproducts,requiring tedious chromatographic separation for the purification of1-formyldipyrromethane (2). The TLC and ¹H NMR analyses of the crudereaction mixture obtained from Vilsmeier formylation of dipyrromethaneshowed the presence of three components: starting dipyrromethane (3),1-formyldipyrromethane (2), 1,9-diformyldipyrromethane (4), and anunknown byproduct (tentatively assigned as a 2-formyldipyrromethane) ina ratio of 7:20:4:1. We were able to separate the desired 2 in 46% yield(without using a tin complexation strategy); however, the purificationrequired lengthy column chromatography.

Given that 2 self-condenses to give Mg-1, and 3+4 undergo reaction togive Mg-1, we decided to examine the porphine-forming reaction with useof the crude mixture derived from Vilsmeier formylation ofdipyrromethane (3), which contains 2, 3, and 4. The crude reactionmixture was concentrated under high vacuum to remove DMF (used as asolvent for Vilsmeier formylation). The resulting mixture was dissolvedin toluene and treated with DBU and MgBr₂ (10 and 3 mol equiv versusdipyrromethane, respectively). The resulting mixture was refluxed untildipyrromethane, 2 and 1,9-diformyldipyrromethane were completelyconsumed (19 h). The chromatography-free purification as described aboveafforded Mg-1 in 33% yield (2.21 g). This streamlined, entirelychromatography-free procedure for the synthesis of Mg-1 offers a simple,practical and fast method for preparing multigram quantities of Mg-1(Scheme 4).

We also investigated the synthesis of Mg-1 directly from the crudedipyrromethane (thereby avoiding the purification of any intermediate).The crude reaction mixture containing dipyrromethane (obtained via 1nCl₃-catalyzed reaction of paraformaldehyde with excess pyrrole²⁶) wasconcentrated under high vacuum and subjected to Vilsmeier formylation.The crude product of Vilsmeier formylation was subsequently used forporphine formation. TLC analysis of the crude reaction mixture revealedthe presence of Mg-1 and the dipyrromethane. The purification of Mg-1 bycrystallization was not successful because of the tarry material in thecrude reaction mixture. Therefore this method is less attractivecompared to the previously described routes.

4. Solubility. One of the intrinsic problems in porphine chemistry isthe poor solubility of 1 in common organic solvents. We compared thesolubility of 1, Pd-1, Zn-1 and Mg-1 in common organic solvents (CH₂Cl₂,THF, MeOH, ethyl acetate, toluene). The general trend in solubility isas follows: Pd-1<1<Zn-1<<Mg-1. The solubility of Mg-1 in common organicsolvents is sufficiently high to perform routine operations(purification, NMR characterization) and perform various reactions atconcentrations (1-50 mM) typical of those for porphyrinic compounds.

5. Synthesis of Porphine 1. A streamlined route to free base porphine 1was examined by demetalation of Mg-1 (Scheme 5). Thus, reaction of 2 inrefluxing toluene containing MgBr₂ and DBU afforded crude Mg-1. Thereaction mixture was concentrated, filtered through an alumina column(to remove excess base and inorganic materials). Treatment of crude Mg-1with dilute TFA in CH₂Cl₂ afforded the free base porphine 1 in 15%overall yield.

Experimental Section

General. ¹H NMR spectra (400 MHz) and ¹³C NMR spectra (100 MHz) werecollected in CDCl₃ at room temperature unless noted otherwise. Silicagel (40 μm average particle size) was used for column chromatography.Anhydrous toluene (Aldrich) was used as received. All other chemicalswere reagent grade and were used as received. The 1-formyldipyrromethane2 is easily detected in TLC upon exposure to Br₂ vapor. Grade V aluminawas prepared by adding 15 mL of H₂O (Fisher GC grade) to 85 g of alumina(Fisher A-540) with manual stirring.

Noncommercial Compounds. 1-Formyldipyrromethane 2,²¹ dipyrromethane 3,²⁶and 1,9-diformyldipyrromethane 4²³ were prepared as described in theliterature. Zn-1 and Pd-1 were prepared previously via differentmethods.²⁵

Yield Determination. In small-scale reaction, the porphine was purifiedand isolated by chromatography. Owing to the small quantity of solidporphine, gravimetry was not performed. Instead, the solid sample wasdissolved in a known volume of solvent, and the yield was determined byabsorption spectrometry, using the molar absorption coefficient of ametalloporphine at the Soret band of 178,800 M⁻¹ cm⁻¹.²⁵ This procedureis referred to as the “yield of isolated porphine determined byabsorption spectrometry”.

Zn(II) porphine (Zn-1). Following a general procedure for porphyrinformation using diformyldipyrromethanes,²³ a sample of 2 (46.0 mg, 0.264mmol) was treated with propylamine (1.00 mL). The resulting mixture wasstirred at room temperature for 1 h and then concentrated to afford abrown oil. The resulting imine was dissolved in EtOH (8.6 mL) andtreated with Zn(OAc)₂ (0.477 g, 2.60 mmol) and refluxed overnight. Thereaction mixture was cooled down, and a sample of DDQ (59.0 mg, 0.264mmol) was added. The resulting mixture was stirred at room temperaturefor 1 h. The mixture was concentrated and chromatographed (silica,CH₂Cl₂) to obtain a purple solid (13%, yield of isolated porphinedetermined by absorption spectrometry): ¹H NMR (THF-d₈) δ 9.55 (s, 8H),10.34 (s, 4H); LD-MS obsd 372.0; FAB-MS obsd 372.0342, calcd 372.0353(C₂₀H₁₂N₄Zn); λ_(abs) 399, 526 nm.

Pd(II) porphine (Pd-1). Following a general procedure for porphyrinformation using 1-acyldipyrromethanes,²² a sample of 2 (0.172 g, 1.00mmol), KOH (0.280 g, 5.00 mmol) and Pd(CH₃CN)₂Cl₂ (0.155 g, 0.600 mmol)was treated with EtOH (10 mL). The resulting suspension was stirred atroom temperature for 1 min and then refluxed for 1 h. The reactionmixture was concentrated and chromatographed (silica, CH₂Cl₂) to obtaina pink-orange solid (22 mg, 11%): ¹H NMR δ 9.46 (s, 8H), 10.38 (s, 4H);LD-MS obsd 414.2; calcd 414.0097 (C₂₀H₁₂N₄Pd); λ_(abs) 393, 503, 536 nm.

Mg(II) porphine (Mg-1). A suspension of 2 (0.174 g, 1.00 mmol) intoluene (10 mL) was treated dropwise with DBU (1.49 mL, 10.0 mmol). Theresulting solution was stirred at room temperature for 5 min and treatedwith a sample of MgBr₂ (0.552 g, 3.00 mmol). The resulting suspensionwas placed in oil bath (preheated to 135° C.) and stirred at 135° C.open to the air for 14 h. The reaction mixture was concentrated undervacuum, dissolved in CH₂Cl₂ and filtered through an alumina column[CH₂Cl₂/ethyl acetate (4:1)→ethyl acetate→CH₂Cl₂/MeOH (5:1)]. Fractionscontaining Mg-1 were collected and concentrated. The resulting oilyresidue was dissolved in CH₂Cl₂. The organic solution was washed withwater and brine, dried (K₂CO₃), concentrated and filtered throughalumina grade V (CH₂Cl₂) to afford a purple solid (67 mg, 41%): ¹H NMR(THF-d₈) δ 9.47 (s, 8H), 10.26 (s, 4H); ¹³C NMR δ 104.8, 131.6, 149.0;LD-MS obsd 331.7; FAB-MS obsd 332.0929, calcd 332.0912 (C₂₀H₁₂N₄Mg);λ_(abs) 402, 536 nm.

Porphine (1). A sample of DBU (6.91 mL, 46.2 mmol, 10.0 mol equiv versus2) was added dropwise to a suspension of 2 (0.805 g, 4.62 mmol, 100 mM)in toluene (46 mL). MgBr₂ (2.55 g, 13.9 mmol, 3.00 mol equiv) was addedto the reaction mixture in a single portion. The reaction mixture washeated to 115° C. (preheated oil bath temperature 115° C.) with exposureto air for 6 h. TLC analysis (silica, CH₂Cl₂/ethyl acetate 1:3) revealedonly a trace amount of starting material. A 1-μL aliquot was removedfrom the reaction mixture and examined by absorption spectroscopy(CH₂Cl₂). Four peaks were observed (302, 383, 403 and 526 nm). The crudereaction mixture was concentrated and chromatographed [alumina grade V,500 g, 4 cm dia×35 cm, loaded with CH₂Cl₂ and eluted with CH₂Cl₂/ethylacetate (4:1→1:1)] afforded a purple solid. The concentrated fractionwas checked by ¹H NMR spectroscopy whereupon ˜10% starting material wasobserved. The concentrated product was dissolved in a minimum amount ofCH₂Cl₂ (˜2 mL). The solution was treated with hexanes (˜15 mL) to afforda precipitate. The mixture was centrifuged. The collected precipitatewas dried under high vacuum and checked by ¹H NMR spectroscopy. Lessthan 5% starting material was observed. The product was dissolved inCH₂Cl₂ (93 mL), and TFA (2.15 mL) was added. The reaction mixture wasstirred vigorously at room temperature for 1 h. The crude reactionmixture was checked by absorption spectroscopy and TLC analysis (silica,CH₂Cl₂). No Mg(II) porphine was observed. The reaction mixture wasneutralized by addition of saturated aqueous NaHCO₃. The organic layerwas washed (water and brine), dried (Na₂SO₄), concentrated, andchromatographed [silica, 200 g, 2 cm dia×30 cm] to afford a purple solid(0.106 g, 15%): ¹H NMR (DMF-d₇) δ (−3.98)-(−3.96) (brs, 2H), 9.80 (s,8H), 10.69 (s, 4H); ¹³C NMR (DMF-d₇) δ 104.5, 132.2-132.3 (brs); LD-MSobsd 309.7; λ_(abs) 396, 490, 564 nm.

Protocol A: Large-scale Synthesis of Mg-1 Directly from1-Formyldipyrromethane at 100 mM. A sample of 1-formyldipyrromethane 2(6.97 g, 40.0 mmol) was placed in a 1000 mL oven-dried round bottomflask. A teflon septum was attached and toluene (400 mL) was added viacannula. The reaction mixture was heated to 80° C., whereupon DBU (60mL, 400 mmol, 10 mol equiv versus 2) was added dropwise under vigorousstirring in 10 mM. The resulting mixture was stirred for 5 min (thetemperature of the reaction mixture increased from 80° C. to 98° C.).The mixture darkened. The septum was removed and MgBr₂ (22.1 g, 120mmol, 3.0 mol equiv versus 2) was added in one portion under vigorousstirring (Note 1). The reaction flask was attached to the refluxcondenser, and heated at 115° C. with exposure to air. On the basis ofTLC analysis (silica, CH₂Cl₂/ethyl acetate 5:1) and absorptionspectroscopy, porphyrin formation was complete in 19 h. The crudereaction mixture was concentrated. The resulting residue was treatedwith THF (400 mL) and stirred vigorously 20 min at room temperature. Thereaction mixture was filtered through a Buchner funnel. The filtrate wasconcentrated (fraction A). The filter cake was mixed with THF (200 mL)and heated to reflux for 1 h (Note 2). The resulting mixture wasfiltered through a Bucher funnel, and the filter cake was washed withTHF (10×10 mL). The collected filtrate was concentrated and combinedwith fraction A. The resulting crude product was combined with ethylether (400 mL), washed [water (200 mL), brine (5×200 mL)] andconcentrated (Note 3). The crude product was purified by crystallization(ethanol/water 1:4). Porphine Mg-1 was obtained as a purple solid (2.68g, 40%).

Note 1: A dry flask is essential, as is vigorous stirring, so that MgBr₂does not reside as a solid on the bottom of the flask, which typicallylowers the yield of porphyrin formation.

Note 2: After the first filtration, some of the magnesium porphinestayed with the filter cake. The cake needs to be heated in THF atreflux to dissolve any remaining porphine.

Note 3: Excess DBU makes the aqueous work-up difficult. A trace amountof MeOH and Na₂SO₄ was used to facilitate phase separation.

Vilsmeier Formylation of Dipyrromethane (3) Affording1-Formyldipyrromethane 2. A sample of DMF (30 mL) was treated with POCl₃(4.5 mL, 49.2 mmol) at 0° C. under argon, and the resulting solution wasstirred for 10 min (Vilsmeier reagent). A solution of 3 (5.84 g, 40.0mmol) in DMF (120 mL) at 0° C. under argon was treated with the freshlyprepared Vilsmeier reagent (25 mL, 41 mmol), and the resulting solutionwas allowed to stir for 1.5 h at 0° C. The reaction mixture was pouredinto a mixture of 2 M NaOH (300 mL) and CH₂Cl₂ (200 mL) at 0° C. A bluecolor was observed. The reaction mixture was stirred for 20 min at 0° C.The reaction mixture turned to orange brown. The organic phase wasextracted with CH₂Cl₂. The collected organic phase was washed with NH₄Cl(200 mL). The organic phase was separated, washed with water and brine,and dried (NaSO₄). The collected organic phase was concentrated to givea red, oily crude product. The remaining DMF was removed under highvacuum (1 h, 50° C.), resulting in a light pink solid material. Thecrude product was purified by column chromatography (silica,CH₂Cl₂→CH₂Cl₂/ethyl acetate 5:1) to give a yellow solid (3.198 g, 46%).The data (¹H NMR, mp, elemental analysis) were consistent with thoseobtained from samples prepared via earlier routes.

Synthesis of Mg-1 Directly from Crude 1-Formyldipyrromethane at 100 mM.Vilsmeier formylation of 3 (5.84 g, 40.0 mmol) was performed followingthe above procedure. The resulting crude pink solid was used for theporphine synthesis without purification. By following Protocol A, thecrude product was dissolved in toluene (400 mL). A sample of DBU (60 mL,400 mmol, 10 mol equiv versus 3) and MgBr₂ (22.1 g, 120 mmol, 3 mol,equiv versus 3) were added. Crystallization of the resulting crudeproduct afforded Mg-1 as a purple solid (2.21 g, 33%). The data (¹H NMR,¹³C NMR, absorption spectrum and FAB-MS) were consistent with thoseobtained from samples prepared via earlier routes.

Synthesis of Mg-1 from 2 at 100 mM. By following Protocol A, a sample of2 (6.97 g, 40.0 mmol) was dissolved in toluene (400 mL). Samples of DBU(60 mL, 400 mmol, 10 mol equiv versus 2) and MgBr₂ (22.1 g, 120 mmol, 3mol, equiv versus 2) were added. Crystallization of the resulting crudeproduct afforded Mg-1 as a purple solid (2.681 g, 40%). The data (¹HNMR, ¹³C NMR, absorption spectrum and FAB-MS) were consistent with thoseobtained from samples prepared via earlier routes.

Synthesis of Mg-1 via 1,9-Diformyldipyrromethane. By following thegeneral procedure, a sample of DBU (0.750 mL, 5.00 mmol) was addeddropwise to a suspension of 3 (36 mg, 0.25 mmol) and 4 (50 mg, 0.25mmol) in toluene (5 mL). MgBr₂ (276 mg, 1.5 mmol, 3.00 mol equiv) wasadded to the reaction mixture in a single portion. The reaction mixturewas heated to 115° C. (preheated oil bath temperature 115° C.) withexposure to air for 36 h. Column chromatography (alumina, grade V,CH₂Cl₂) afforded Mg-1 in 18% yield.

TABLE 1 Reported Methods for Porphine Synthesis. Isolated Yield EntryStarting material Conditions product (mg) (%) Ref. 1

HCOOH, reflux  17 0.1  6 2

propionic acid, pyridine 95° C. pyridine/MeOH sealed tube 130       ~30.9     ~0.02  8      7 3

Ethylbenzene 100° C., 11.5 days (1) 4-methyl-2- pentanone/AcOH/H₂O (2)DDQ DMF, pH = 3.7 145° C. various metal salt H₂O/AcOH Mg(OAc)₂ (0.2%)potassium persulfate (1) HCl, H₂O/SDS^(c) (2) DDQ NR^(a)    30     Up to200        0.3      2 18.02   15.3      Up to 20.3^(b )    5.33     2  10   12     11      9     13 4

(1) EtMgBr, chlorobenzene 180° C. (2) Cu(OAc)₂, AcOH  12  3.86 14 5

(1) BF₃•MeOH (2) p-chloranil NR 31^(c )   18 6

H₂SO₄/1-butanol 90° C., 15 min  86 74   16 7

H₂SO₄ 200° C., 15 min  74 64   17 ^(a)Not reported. ^(b)This yield isclaimed to be non-reproducible; see reference 12. ^(c)SDS—sodium dodecylsulfate. ^(d)Yield was determined by absorption spectroscopy.

REFERENCES

-   (1) Nudy, L. R.; Coffey, J. C.; Longo, F. R. J. Heterocyclic Chem.    1982, 19, 1589-1560.-   (2) Shi, D.-F.; Wheelhouse, R. T. Tetrahedron Lett. 2002, 43,    9341-9342.-   (3) Schlozer, R.; Fuhrhop, J.-H. Angew. Chem. Int. Ed. 1975, 14,    363-363.-   (4) Hatscher, S.; Senge, M. O. Tetrahedron Lett. 2003, 44, 157-160-   (5) Neya, S.; Funasaki, N. J. Biol. Chem. 1993, 268, 8935-8942.-   (6) Fischer, H.; Gleim, W. Liebigs Ann. 1936, 521, 157-160.-   (7) Rothemund, P. J. Am. Chem. Soc. 1935, 57, 2010-2011. (b)    Rothemund, P. J. Am. Chem. Soc. 1936, 57, 625-627.-   (8) Neya, S.; Yodo, H.; Funasaki, N. J. Heterocyclic Chem. 1993, 30,    549-550.-   (9) Krol, S. J. Org. Chem. 1959, 24, 2065-2067.-   (10) Longo, F. R.; Thorne, E. J.; Adler, A. D.; Dym, S. J.    Heterocyclic Chem. 1975, 12, 1305-1309.-   (11) Yalman, R. G. U.S. Pat. No. 3,579,533.-   (12) Ellis, P. E.; Langdale, W. A. J. Porphyrins Phthalocyanines    1997, 1, 305-307.-   (13) Bonar-Law, R. P. J. Org. Chem. 1996, 61, 3623-3634.-   (14) Eisner, U.; Linstead, R. P. J. Chem. Soc. 1955, 3742-3749.-   (15) Egorova, G. D.; Solov'ev, K. N.; Shul'ga, A. M. J. Gen. Chem.    (USSR) 1967, 37, 333-336.-   (16) Neya, S.; Quan, J.; Hoshino, T.; Hata, M.; Funasaki, N.    Tetrahedron Lett. 2004, 45, 8629-8630.-   (17) Neya, S.; Funasaki, N. Tetrahedron Lett. 2002, 43, 1057-1058.-   (18) Taniguchi, S.; Hasegawa, H.; Nishimura, M.; Takahashi, M.    Synlett 1999, 73-74.-   (19) Rao, P. D.; Littler, B. J.; Geier, G. R., III;    Lindsey, J. S. J. Org. Chem. 2000, 65, 1084-1092.-   (20) Zaidi, S. H. H.; Fico, R. M., Jr.; Lindsey, J. S. Org. Process    Res. Dev. 2006, 10, 118-134.-   (21) Ptaszek, M.; McDowell, B. E.; Lindsey, J. S. J. Org. Chem.    2006, 71, 4328-4331.-   (22) Sharada, D. S.; Muresan, A. Z.; Muthukumaran, K.;    Lindsey, J. S. J. Org. Chem. 2005, 70, 3500-3510.-   (23) Taniguchi, M.; Balakumar, A.; Fan, D.; McDowell, B. E.;    Lindsey, J. S. J. Porphyrins Phthalocyanines 2005, 9, 554-574-   (24) Woodford, J. N.; Lindsey, J. S. Inorg. Chem. 1995, 34,    1063-1069.-   (25) Barth, G.; Linder, R. E.; Waespe-Sarcevic, N.; Bunnenberg, E.;    Djerassi, C.; Aronowitz, Y. J.; Gouterman, M. J. Chem. Soc. Perkin    Trans. 2 1977, 337-343.-   (26) Laha, J. K.; Dhanalekshmi, S.; Taniguchi, M.; Ambroise, A.;    Lindsey, J. S. Org. Process Res. Dev. 2003, 7, 799-812.

The foregoing is illustrative of the present invention, and is not to beconstrued as limiting thereof. The invention is defined by the followingclaims, with equivalents of the claims to be included therein.

1.-7. (canceled)
 8. A method of making a compound of Formula I:

comprising: condensing (i) a compound of Formula III with a compoundFormula IV:

with (ii) a metal salt under basic conditions to produce said compoundof Formula I; wherein: said metal salt is a magnesium, zinc, nickel, orindium salt; each X is independently selected from the group consistingof O, S, Se, NH, NR, (OR)₂, (SR)₂, and (SeR)₂, wherein R is as givenbelow; each A is independently selected from the group consisting of: H,alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl,cycloalkylalkynyl, heterocyclo, heterocycloalkyl, heterocycloalkenyl,heterocycloalkynyl, acetal, aryl, aryloxy, arylalkyl, arylalkenyl,arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl,heteroarylalkynyl, alkoxy, halo, mercapto, azido, cyano, acyl, formyl,carboxylic acid, acylamino, ester, amide, hydroxyl, nitro, alkylthio,amino, alkylamino, arylalkylamino, disubstituted amino, acyloxy,sulfoxyl, sulfonyl, sulfonate, sulfonic acid, sulfonamide, urea,alkoxylacylamino, aminoacyloxy, linking groups, surface attachmentgroups, bioconjugatable groups, targeting groups, and water solublegroups; each B is independently selected from the group consisting of:H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkenyl, cycloalkylalkynyl, heterocyclo, heterocycloalkyl,heterocycloalkenyl, heterocycloalkynyl, acetal, aryl, aryloxy,arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl,heteroarylalkenyl, heteroarylalkynyl, alkoxy, acyl, formyl, carboxylicacid, acylamino, alkylthio, amino, alkylamino, arylalkylamino,disubstituted amino, linking groups, surface attachment groups,bioconjugatable groups, targeting groups, and water soluble groups; eachR is independently selected from the group consisting of: H, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl,cycloalkylalkynyl, heterocyclo, heterocycloalkyl, heterocycloalkenyl,heterocycloalkynyl, acetal, aryl, aryloxy, arylalkyl, arylalkenyl,arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl,heteroarylalkynyl, alkoxy, halo, mercapto, azido, cyano, acyl, formyl,carboxylic acid, acylamino, ester, amide, hydroxyl, nitro, alkylthio,amino, alkylamino, arylalkylamino, disubstituted amino, acyloxy,sulfoxyl, sulfonyl, sulfonate, sulfonic acid, sulfonamide, urea,alkoxylacylamino, aminoacyloxy, linking groups, surface attachmentgroups, bioconjugatable groups, targeting groups, and water solublegroups; or an adjacent pair of two R groups may together form anannulated arene or annulated alkene.
 9. The method of claim 8, whereinsaid metal salt is a magnesium or zinc salt.
 10. The method of claim 8,wherein said metal salt is a magnesium halide.
 11. The method of claim8, further comprising the step of displacing said metal to form a freebase of said compound of Formula I.
 12. The method of claim 8, whereinsaid condensing step is carried out by microwave irradiation.
 13. Themethod of claim 8, wherein said condensing step is carried out in anon-coordinating or weakly coordinating solvent.
 14. The method of claim8, wherein said condensing step is carried out in a non-coordinating orweakly coordinating solvent in the presence of a non-coordinating orweakly coordinating base.
 15. A method of making porphine, comprising:condensing (a) (i) 1-formyl dipyrromethane with itself, (ii), condensing1,9-diformyldipyrromethane with dipyrromethane, or (iii) concurrentlyboth condensing 1-formyl dipyrromethane with itself while alsocondensing 1,9-diformyldipyrromethane with dipyrromethane, with (b) ametal salt under basic conditions to produce said porphine; wherein saidmetal salt is a magnesium, zinc, nickel or indium salt.
 16. The methodof claim 15, wherein said condensing comprises condensing 1-formyldipyrromethane with itself.
 17. The method of claim 15, wherein saidcondensing comprises condensing 1,9-diformyldipyrromethane withdipyrromethane.
 18. The method of claim 15, wherein said condensingcomprises concurrently condensing 1-formyl dipyrromethane with itselfwhile also condensing 1,9-diformyldipyrromethane with dipyrromethane.19. The method of claim 15, wherein said metal salt is a magnesium orzinc salt.
 20. The method of claim 15, wherein said metal salt is amagnesium halide.
 21. The method of claim 15, further comprising thestep of displacing said metal to form free base porphine.
 22. The methodof claim 15, wherein said self-condensing step is carried out bymicrowave irradiation.
 23. The method of claim 15, wherein saidself-condensing step is carried out in a non-coordinating or weaklycoordinating solvent.
 24. The method of claim 15, wherein saidself-condensing step is carried out in a non-coordinating or weaklycoordinating solvent in the presence of a non-coordinating or weaklycoordinating base.